Non Invasive Free Radical MRI in Stroke

非侵入性自由基 MRI 治疗中风

• 批准号: 8682146
• 负责人: Matthew Scot Rosen
• 金额: $ 25.16万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8682146
• 关键词: Accounting; Acute; Biological; Biological Markers; Blood - brain barrier anatomy; Brain; Brain Injuries; Cause of Death; Cell Death; Cerebral Infarction; Cerebral Ischemia; Clinical Treatment; Clinical assessments; Contrast Media; Detection; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Electron Spin Resonance Spectroscopy; Electrons; Environment; Extravasation; Free Radicals; Frequencies; Gadolinium DTPA; Generations; Goals; Hemorrhage; Hour; Image; Imaging Techniques; In Vitro; Individual; Infarction; Inflammation; Injection of therapeutic agent; Injury; Intervention; Ischemia; Ischemic Stroke; Kinetics; Life; Link; Magnetic Resonance Imaging; Measures; Mediating; Methodology; Methods; Middle Cerebral Artery Occlusion; Modeling; Monitor; Organism; Oxidative Stress; Patients; Pattern; Performance; Physiologic pulse; Pilot Projects; Process; Production; Radio; Rattus; Reactive Oxygen Species; Recurrence; Relaxation; Reperfusion Injury; Reperfusion Therapy; Resolution; Risk; Rupture; Scientist; Staging; Stroke; Techniques; Technology; Testing; Therapeutic; United States; Work; acute stroke; base; cell injury; clinical application; clinically relevant; disability; excitotoxicity; experience; high risk; imaging modality; improved; in vivo; innovation; insight; interest; novel; prognostic; public health relevance; research clinical testing; small molecule; spatiotemporal; tempol; tool

DESCRIPTION (provided by applicant): Stroke is a leading cause of death and disability. Free radical generation is a well-documented mechanism of ischemia/reperfusion injury, blood brain barrier (BBB) disruption and hemorrhage in ischemic stroke. However, free radicals are difficult to study due to lack of non-invasive tools for in vivo assessment. Conventional MRI is widely used for diagnostic imaging; however, it offers no window into the fundamental processes of oxidative stress following reperfusion injury. There are currently no NMR contrast mechanisms that can detect endogenous production of destructive free radicals. MRI-based biomarkers for visualizing and quantifying the BBB disruption at very early (hyperacute) stages of stroke are similarly unavailable as MRI contrast agents such as Gd-DTPA can only probe ischemic BBB disruption several hours after stroke onset. Free radical sensitive Overhauser-enhanced MRI (OMRI) is a promising technique for imaging the distribution and dynamics of free radicals. We have recently demonstrated a novel, fast and high-resolution OMRI method that offers new perspectives for the free radicals imaging in living organisms. We propose here two complementary aims to implement this novel MRI-based method for non-invasive 3D free radical imaging in ischemic stroke: Aim 1: Detect endogenous free radical production by OMRI as a novel and direct measure of oxidative stress associated with ischemia/reperfusion injury. Aim 2: Detect hyperacute BBB breakdown by making use of a stable free radical probe (TEMPOL) as an exogenously administered contrast agent for OMRI. We will use a rat model of cerebral ischemia/reperfusion to test and refine the ability of our technique to detect endogenous and exogenous free radicals. Both aims have direct clinical relevance. In vivo OMRI of endogenous free radical production will open a non-invasive window into oxidative stress and reperfusion injury, a critical mechanism of cell death in stroke and other forms of brain injury. OMRI will provide an in-depth understanding of spatiotemporal patterns of endogenous free radical production in ischemic brain. Moreover, timely detection of oxidative stress will help tailor interventions to mitigate free radical-induced brain injury in individual patients. Additionally, the use of TEMPOL as a small, exogenous OMRI agent will allow monitoring BBB disruption in stroke at the hyperacute stage, much earlier than the traditional relaxation-based MRI contrast agents that rely on the leakage of larger molecules (such as Gd-DTPA) across the BBB. Altogether, the OMRI technology is a tool that may transform the diagnostic, therapeutic and prognostic approach to acute stroke.

描述（由申请人提供）：中风是死亡和残疾的主要原因。自由基的产生是缺血/再灌注损伤、血脑屏障（BBB）破坏和缺血性中风出血的一种有据可查的机制。然而，由于缺乏用于体内评估的非侵入性工具，自由基很难研究。常规 MRI 广泛用于诊断成像；然而，它并没有提供了解再灌注损伤后氧化应激基本过程的窗口。目前还没有核磁共振对比机制可以检测破坏性自由基的内源性产生。同样，基于 MRI 的生物标志物无法在中风极早期（超急性）阶段可视化和量化 BBB 破坏，因为 Gd-DTPA 等 MRI 造影剂只能在中风发作后数小时探测缺血性 BBB 破坏。自由基敏感的奥弗豪瑟增强 MRI (OMRI) 是一种有前途的自由基分布和动态成像技术。我们最近展示了一种新颖、快速、高分辨率的 OMRI 方法，为活体中的自由基成像提供了新的视角。我们在此提出两个互补的目标，以实施这种基于 MRI 的新型方法，在缺血性中风中进行非侵入性 3D 自由基成像： 目标 1：通过 OMRI 检测内源性自由基的产生，作为与缺血/再灌注相关的氧化应激的一种新颖且直接的测量方法受伤。目标 2：利用稳定的自由基探针 (TEMPOL) 作为 OMRI 的外源性造影剂来检测超急性 BBB 破裂。我们将使用脑缺血/再灌注的大鼠模型来测试和完善我们的技术检测内源性和外源性自由基的能力。这两个目标都具有直接的临床相关性。内源性自由基产生的体内 OMRI 将为氧化应激和再灌注损伤打开一个非侵入性窗口，氧化应激和再灌注损伤是中风和其他形式脑损伤中细胞死亡的关键机制。 OMRI 将深入了解缺血性大脑中内源性自由基产生的时空模式。此外，及时检测氧化应激将有助于制定干预措施，以减轻个体患者自由基引起的脑损伤。此外，使用 TEMPOL 作为一种小型外源性 OMRI 试剂将允许在超急性阶段监测中风的 BBB 破坏，比传统的基于松弛的 MRI 造影剂（依赖于较大分子的泄漏，如 Gd-DTPA）早得多。 ）穿过BBB。总而言之，OMRI 技术是一种可以改变急性中风的诊断、治疗和预后方法的工具。